Bicyclic imidazoles

ABSTRACT

Compounds of the class of imidazo(1,2-a)imidazoles, imidazo(1,2a)pyridimidines and pyrimido(1,2-a)pyrimidines useful as central nervous system (CNS) antidepressants; and certain novel precursors therefor.

United States Patent [1 1 Van Gelder et al. 1

1451 Feb. 11,1975

[ BICYCLIC IMIDAZOLES [75] Inventors: Josephus Ludovicus Hubertus VanGelder; Alfons Herman Margaretha Raeymaekers, both of Beerse; RoevensLeopold Frans Corneel, Rijkevorsel; Willy Joannes Van Laerhoven, Ravels,all of Belgium [73] Assignee: Janssen Pharmaceutica N.V.,

Beerse, Belgium 22 Filed: Dec. 8, 1972 211 App]. No.: 313,285

[56] References Cited FOREIGN PATENTS OR APPLICATIONS 796,996 6/1958Great Britain 260/3096 805.877 12/1958 Great Britain ..260/309.6

OTHER PUBLICATIONS Kochergin et al., Chem. Abst., 1969. Vol. 71, No.332Sm Kreling et al., Chem. Abst., 1958, Vol. 52, columns 17281-17282Miller et al., J. Med. Chem., 1972, Vol. 15, No. 4, pages 415-417Primary Examiner-Natalie Trousof Attorney, Agent, or FirmSalvatore R.Conte [57] ABSTRACT Compounds of the class of imidazo[1,2-a]imidazoles,imidazol l ,2-a]pyridimidines and pyrimido[1,2- alpyrimidines useful ascentral nervous system (CNS) antidepressants; and certain novelprecursors therefor.

, 16 Claims, N0 Drawings BICYCLIC IMIDAZOLES BACKGROUND OF THE INVENTIONThe invention pertains to the field of bicyclic imidazoles and bicyclicpyrimidines having an aryl substituent in a certain position-describedhereinafter. The prior art discloses certain bicyclic rings but not withthe designated aryl substituent insaid position. Such other compoundswill be found in the following references:

I. Miller et al., J. Med. Chem, 15, (4), 4l5 (I972);

2. C.A. 52, 7333i (1958);

3. C.A. 52, I728Ii (1958);

4. C.A. 54, 19727d (I960);

5. C.A. 52, 1470Ie (1958); and

6. C.A. 52, 445i (1958).

PREFERRED EMBODIMENTS The novel bicyclic imidazoles and pyrimidines ofthis invention may be structurally represented by the folwherein m isthe integer zero or I;

wherein n is the integer zero or I;

wherein R is a member selected from the group consisting of hydrogen andbenzyl;

wherein R is a member selected from the group consisting of hydrogen andloweralkyl, preferably methyl, provided that, when said R is loweralkyl,then said n is zero; and

wherein Ar is a member selected from the group consisting of phenyl,loweralkylphenyl, halophenyl and dihalophenyl.

The therapeutically active non-toxic acid addition salts of theforegoing compounds (I) are also embraced within the scope of thisinvention.

As used herein, loweralkyl may be straight or branch chained and havefrom I to 5 carbon atoms, such as, for example, methyl, ethyl, propyl,isopropyl, butyl, tert-butyl, pentyl and the like alkyls. The pre ferredloweralkyl is methyl. the term halo" refers to halogens of atomic weightless than 127, i.e., chloro, bromo, fluoro and iodo.

When R is hydrogen, the subject compounds (I) exhibit tautomerism due tothe migration of the corresponding proton between the two nitrogens asfollows:

( lif K N III-CfH-(CH C-Ar The compounds of formula (II), where R ishydrogen, are conveniently prepared by the reaction of an appropriateZ-nitroamino-imidazoline or 2- nitroaminotetrahydro pyrimidine offormula (III), wherein m is the integer zero or I, with an appropriatea-(aminoalkyU-benzyl alcohol of formula (IV), wherein n, R and Ar are aspreviously defined, in a suitable inert organic solvent. Typicalsolvents that may be employed are aromatic hydrocarbons, e.g., benzene,toluene, xylene and the like, and ethers, e.g., dioxane and themonoethyl and diethyl ethers of ethane diol. Elevated temperatures maybe employed to enhance the rate of reaction. The foregoing; reactionsmay be illustrated as follows:

To prepare the compounds of formula (II), in which R is benzyl, anappropriate 2-benzylamino-imidazoline or 2-benzylamino-pyrimidine offormula (VI), wherein m is zero or I, is reacted with an appropriatearoyl alkyl halide, preferably the bromide, of formula (VII), wherein Arand n are as previously described, in a suitable organic solvent suchas, for example, an aromatic hydrocarbon, e.g., benzene, toluene, xyleneand the like, an ether, e.g., dioxane, diethyl ether, tetrahydrofuranand the like, and a lower alkanone, e.g., acetone, methyl ethyl ketoneand the like. If desired, a stoichiometric excess of basic (VI) or ahalogen acid scavenger may be added to pick up the halogen acid that isIiberated during the course of thereaction. The carbonyl function of thethus-obtained condensation product (VIII) is reduced to a carbinolfunction (IX) by treatment with suitable reducing agents, such as sodiumborohydride and the like. The foregoing reactions are illustrated asfollows:

An alternative method of making the imidazol l,2-a]- imidazolines andimidazol I ,2-a]pyrimidines of formula (I), wherein n is O and R=R=hydrogen, is through the following synthetic sequence. An appropriatenitrostyrene of formula (X), wherein Ar is as previously defined, isreacted with an appropriate aminoalkanol of formula (XI), wherein m isthe integer zero or I, in a suitable inert organic solvent and,preferably, in the cold (0-5C). The thus-obtained nitro-alcohol base offormula (XII), which may be conveniently isolated by conventionaltransformation into an acid addition salt, for example, by treatmentwith alkanolic I-ICI, is then subjected to catalytic hydrogenation toafford the corresponding amino-alcohol of formula (XIII), which may alsobe similarly isolated in the form of an acid addition salt. The lattercompound (XIII) is treated with Ar-CH=CH-NO 'mu la(XV) is accomplishedby conventional methyliodide treatment. The Z-methylthio function istransformed into a 2-amino function (XVI) by treatment with ammonia. Thehydroxy function is replaced with a chloro function (XVII) by treatmentwith thionyl chloride, preferably at reflux temperatures in a suitableorganic solvent such as, for example, chloroform. Ring closure into thedesired bicyclic product (XVIII) is accomplished by treatment withalkali metal, e.g., sodium, in a suitable solvent, e.g., methanol, underreflux. The foregoing reaction sequence may be schematically illustratedas follows:

(XII) 1. H2, Raney-Ni CH2'NH2 2. HCl ArCH-NHCH (CH -OH (XIII) 1. NaOH Hs 9 N Ar NCH -(CH OH Mel metnanol (XIV) LJ-l-ue 1 \I\\ l \l v 1 ArInl'3[ rl2((.ll on l fi N 2 AILL-.. -cH -(CH -0El r11 (XVI) N 3H2 ML NCH(CH -Cl HCl E (XVII) H 1- N N1 .N /N I Q ll Ar N 2)m A .i: N 2)m (XVIII)(XVIII) The subject compounds of formula (I) have been found to possessuseful pharmacological properties as 55 demonstrated in one or more ofthe following tests indicative of CNS antidepressant activity. Test A.Amphetamine test in rats:

An intravenous injection of 5 mg/kg of dextroamphetamine in rats inducespronounced CNS-stimulating 60 effects that are characterized bystereotyped chewing movements, agitation and exophthalmia. These effectslast for about 1 to 1 /2 hour after treatment. Pretreatment withantidepressants gives a prolongation of these typical effects which arestill observable up to 4 hours 65 after the injection ofdextroamphetamine. The dose level at which the tested compoundpotentiates these effects of amphetamine is recorded.

graph. Following a stabilization time of l5 minutes,

noradrenaline is added to the bath-solution at 6-minute intervals. Thedrug to be tested is added to the Tyrodesolution and the interactionwith noradrenalineinduced contractions is measured. Drug effect iscalled potentiation if the noradrenaline-induced contraction obtained inthe presence of the drug exceeds the response to noradrenalinepreviously obtained. The dose of the drug, expressed in mg per liter,which potentiates the noradrenaline response is recorded.

In the following table, the CNS antidepressant profile of several of thesubject compounds is listed, as demonstrated by their relative responsesto the aforementioned tests. It is understood that the compounds listedtherein are not stated for purposes of limiting the invention thereto,but only to show the useful properties of all the compounds within thescope of formula (1).

TABLE 1.

Antitetrabenazine test Test a tlextro isomer of Example 1 Compound 11levo isomer of Example 1 Compound Due to the assymetric carbons presentin the subject compounds (1), it is evident that their existence in theform of stereochemical isomers (enantiomorphs) is possible. If desired,the resolution and isolation or the production of a particular form canbe accomplished by application of general principles and technqiuesknown in the art. Such pharmacologically active enantiomorphs arenaturally intended to be included within the scope of this invention.

The organic bases of formula (I) may be converted to the correspondingpharmaceutically acceptable acid addition salts by reaction with anappropriate inorganic acid, such as, for example, hydrochloric,hydrobromic, hydroiodic, sulfuric and the like acids, or with anappropriate organic acid, such as, for example, acetic, propionic,glycolic, lactic, oxalic, malonic, tartaric, citric, sulfamic, ascorbicand the like acids. In turn, the acid addition salts may be converted tothe correspond ing base form by conventional treatment with suitablealkali.

The preferred compounds herein are those of formula (l) in which m and nboth equal zero, and R and R both equal hydrogen, which compounds may beillustrated by the formula:

ran

and denoted as 2,3.5,6-tetrahydro-3(5l-Ar-lH- imidazol1,2-a]imidazoles.The most preferred species are those in which Ar is phenyl andfluorophenyl.

The compounds of formulas (11) and (Vlll) are deemed to be novel and. inview of their utility as precursors in the synthetic procedurespreviously described, such compounds constitute an additional feature ofthis invention.

The following examples are intended to illustrate and not to limit thescope of the present invention. Unless otherwise stated, all parts areby weight.

EXAMPLE 1 A mixture of 15.8 parts B-hydroxy-phenethyl-amine, 13 parts2-nitramino-2-imidazoline and 8 parts xylene is stirred and heated for30 minutes at 160C. (oilbath). After cooling the reaction mixture to atemperature of about C., there are added 40 parts acetone. The whole isfiltered warm and after cooling the filtrate to room temperature, theprecipitated product is fil tered off and dried, yieldingZ-(B-hydroxy-phenethyL amino)-2-imidazoline; m.p. 147l49C.

To parts thionylchloride (previously cooled to 0C.) are added 10.15parts Z-(B-hydroxy-phenethylamino)-2-imidazoline. After the addition iscomplete, the whole is stirred for 30 minutes at room temperature andfurther stirred and refluxed for 15 minutes. The solvent is evaporated.The residue is dissolved in 40 parts toluene and evaporated again. Thistreatment is repeated by using 40 parts methanol. The residue is thendissolved in 40 parts 2-propanol. To this solution is added a solutionof 1.15 parts sodium metal in 40 parts 2-propanol. The whole is stirredand refluxed for one hour. The solvent is evaporated. The residue isdissolved in 150 parts water. The solution is filtered. The filtrate isalkalized with ammonium hydroxide and extracted three times with 40parts ether and three times with 75 parts chloroform. The combinedextracts are dried over potassium carbonate and evaporated. The solidresidue is recrystallized from a mixture of 16 parts acetone and 16parts 4 -methyl-2-pentanone, yielding2,3,5,-tetrahydro-S-phenyl-1H-imidazo[1,2- a]imidazole; m.p. 167-l69.5C.

EXAMPLE ll Three parts of 2-(B-hydroxyphenethylamino)-2- imidazoline areadded portionwise to 1 1 parts of concentrated sulfuric acid solution at0C. The whole is stirred at room temperature for 2 hr. 30 minutes andpoured onto crushed ice. The formed precipitate is filtered off and thefiltrate is alkalized with sodium hydroxide. The product is extractedthree times with chloroform (once with 75 parts and twice with 150parts). The combined extracts are dried and evaporated. The residue istriturated in acetone, treated with activated charcoal, filtered and thefiltrate is evaporated. The residue is converted into the hydrochloridesalt in 4-methyl-2-pentanone. The precipitated salt is filtered off,washed with 2-propanol and dried, yielding2,3,5,6-tetrahydro-5-phenyl1H-imidazo[1,2- a]imidazole hydrochloride,m.p. 227.5-229C.

EXAMPLE 111 A mixture of 6.5 parts of a-( l-aminoethyl)benzyl alcohol(also known as morephedrine), 5.2 parts of Z-(nitramino)-2-imidazolineand 8 parts of xylene is stirred for 30 minutes while heating at 170C.

The reaction mixture is cooled and diluted with acetone. The latter isremoved in vacuo, yielding a[ l-(2- imidazolin-2-ylamino)-ethyl]benzylalcohol as an oily residue.

A solution of 12 parts of the oily a-[ l-(2-imidazolin-2-ylamino)ethyl]benzyl alcohol in 40 parts of sulfuric acid solution 80%is stirred for 3 hours at room temperature. The reaction mixture ispoured onto crushed ice. The whole is alkalized with sodium hydroxidesolution and the product is extracted with toluene. The extract isdried, filtered and evaporated. The residue is washed with acetone anddried, yielding 2,3,5,6-tetrahydro-2- methyl-3-phenyll H-imidazol l,2-a]imidazole; m.p. 179.4C.

EXAMPLE IV To a stirred solution of 8 parts of a-(aminomethyl)-3,4-dichlorobenzyl alcohol in 4.5 parts of xylene are added 5.2 parts of2(nitramino)-2-imidazo1ine. The whole is heated in an oil-bath at atemperature of about 160C. till a clear melt is obtained (aboutminutes). After cooling to about 60C., the melt is dissolved in acetoneand allowed to crystallize. The precipitated product is filtered off andrecrystallized from parts of 4-methyl-2-pentanone, yielding3,4-dichloro-a-(2- imidazolin-2-ylaminomethyl)benzyl alcohol; m.p. 148C.

4.3 parts of 3,4-dichloro-a-(2-imidazolin-2- ylaminomethyl)benzylalcohol are added portionwise to 16.2 parts of sulfuric acid solution80% while stirring and cooling. Upon completion, the mixture is stirredfor 2 hr. min. at room temperature. The reaction mixture is poured ontoice-water, alkalized with concentrated sodium hydroxide solution and theproduct in base form is extracted with methylene chloride. The organiclayer is dried, filtered and evaporated. The residue is converted intothe hydrochloride salt in 2- propanol, yielding5-(3,4-dichlorophenyl)-2,3,5,6- tetrahydrol H-imidazo[ 1,2-a]imidazolehydrochloride; m.p. 298.4C (dec.).

EXAMPLE V To a solution of 6.5 parts of a-(aminomethyU-pfluorobenzylalcohol in 8 parts of xylene are added 5.2 parts of2-(nitramino)-2-imidazoline. The mixture is heated in an oil-bath toabout 160C. till gas-evolution is ceased (about 15 minutes). Thereaction mixture is cooled and treated with benzene and acetone. Theproduct is sucked off and crystallized from 4-methyl-2- pentanone,yielding p-fluoro-a-(2-imidazolin-2- ylaminomethyl)benzyl alcohol; m.p.153.4C.

To 18 parts of sulfuric acid 80% are added portionwise 2 parts ofp-fluoro-a-(2-imidazolin-2- ylaminomethyl)-benzyl alcohol while coolingand stirring in an ice-bath. Upon completion, stirring is continued for2 hr. 15 min. at room temperature. The reaction mixture is poured ontoice-water, diluted with water till a volume of 150 parts, alkalized withconcentrated sodium hydroxide solution and the product in base form isextracted with methylene chloride. The extract is dried and evaporated.The residue is converted into the hydrochloride salt. yieldingS-(pfluorophenyl)-2.3,5,6-tetrahydro-lH-imidazo[1,2- alimidazolehydrochloride; m.p. 259.8C.

EXAMPLE Vl To 5.2 parts of 2(nitramino)-2-imidazoline is added asolution of 7.5 parts of a-(aminomethyH-p chlorobenzyl alcohol in 40parts of xylene while heat ing. Upon completion, stirring is continuedwhile heating in an oil-bath at l50160C. and while the xylene is partlydistilled off (till gas evolution ceases). The residue is cooled andafter the addition of a few parts of acetone, the product is allowed tocrystallize. It is filtered off. washed successively with acetone anddiisopropylether, dried and the product is recrystallized from4-methyl-2-pentanone. yielding p-chloro-oz-(Z-imidazolin-Z-ylaminomethyl )benzzyl alcohol; m.p. 156 1 58C.

3.4 parts of p-chloro-ot-(Z-imidazolin-Z- ylaminomethyl)benzyl alcoholare added to 30 parts of sulfuric acid while stirring and cooling in anice bath. Upon completion, the whole is stirred for 2 hours at roomtemperature. The reaction mixture is poured onto crushed ice, alkalizedwith a concentrated sodium hydroxide solution and the product in baseform is extracted with methylene chloride. The extract is dried,filtered and evaporated. The residue is dissolved in 2- propanol. Thesolution is filtered over diatomaceous silica and the filtrate isacidified with an excess of 2- propanol previously saturated withgaseous hydrogen chloride. The precipitated salt is filtered off, washedwith acetone and dried, yielding 5-(p-chlorophenyl)-2,3,5,6-tetrahydro-l H-imidazo[ 1 ,2-a]imidazole hydrochloride, m.p.266.lC.

EXAMPLE Vll A mixture of 8.2 parts of a-(aminomethyU-mmethylbenzylalcohol, 6,1 parts of 2-(nitramino)-2- imidazoline and 40 parts ofxylene is stirred in an oil-- bath at l50160C, while almost all xyleneis distilled off. The residue is diluted with a few parts of acetone andallowed to crystallize. The product is filtered off and recrystallizedfrom 4-methyl-2-pentanone, yieldinga-(2-imidazolin-2-ylaminomethyll-m-methylbenzyl alcohol; m.p. 121C.

4 parts of a-(Z-imidazolin-2-ylaminornethyD-mmethylbenzyl alcohol areadded portionwise to 36 parts of sulfuric acid solution 80% whilecooling in an icebath. The mixture is stirred for 2 hours at roomtemperature. The reaction mixture is poured onto crushed ice and theresulting solution is alkalized with sodium hydroxide solution at roomtemperature (cooling with ice is necessary). The product in base form isextracted with chloroform. The extract is converted into thehydrochloride salt in 2-propanol, yielding 2,3,5,6-tetrahydro-S-m-tolyl-1I-l-imidazo[1,2-a]imidazole hydrochloride; m.p.269.lC. (dec.).

EXAMPLE Vlll A mixture of 9.5 parts of a-(aminomethyl)-mchlorobenzylalcohol, 7.15 parts of 2-(nitramino)-2- imidazoline and 40 parts ofxylene is stirred in an oilbath at l50160C. while a great part of thexylene is distilled off. The resulting residue is diluted with a fewparts of acetone and the product is allowed to crystallize. It isfiltered off and crystallized from 4-methyl-2- pentanone, yieldingm-chloro-cv-(2-imidazolin-2- ylaminomethyl)benzyl alcohol; m.p. 108.5C.

4 parts of m-chloro-a-(Z-imidazolin-Z- ylaminomethyl)benzyl alcohol areadded portionwise to 21) parts of cooled (ice-bath) sulfuric acidsolution 80%. Upon completion, the whole: is stirred for 2 hours at roomtemperature. The reaction mixture is poured onto crushed ice and thewhole is filtered over diatomaceous silica. The filtrate is alkalizedwith ammonium hydroxide solution at room temperature (cooling is EXAMPLE[X A mixture of 9.06 parts of a-(aminomethyl)-pmethylbenzyl alcohol, 7.8parts of 2-(nitramino)-2- imidazoline and 8 parts of xylene is stirredfor 30 minutes at 160C (oil-bath). The reaction mixture is cooled andacetone is added. The precipitated product is filtered off, washed withacetone and dried, yielding a-(2-imidazolin-2-ylaminomethyl)-p-methylbenzyl alcohol; 163.7C.

A solution of parts of a-(Z-imidazolin-Z- ylaminomethyl)-p-methylbenzylalcohol in 45 parts of concentrated sulfuric acid is stirred overnightat room temperature. The reaction mixture is poured onto water,alkalized with sodium hydroxide and the product is extracted withtoluene. The extract is dried and evaporated. The oil residue is stirredin acetone and the solid base product is filtered off. It is convertedinto the hydrochloride salt in 2-propanol, yielding 235,6-tetrahydro-3-p-tolyl-l H-imidazo-[ l,2-a]imidazole hy drochloride; m.p.254.2C.

EXAMPLE X A mixture of 7.2 parts of l,4,5,6-tetrahydro-2-'nitraminopyrimidine, 7.55 parts of ot-(aminomethyl)- benzyl alcohol and12 parts of xylene is stirred and refluxed for 4 hours on a water-tap.The xylene is evaporated and the residue is dissolved in parts ofacetone. The product is crystallized at room temperature. It is filteredoff and dried, yielding a-(l,4,5,6-tetrahydro-Z-pyrimidinylaminomethyl)benzyl alcohol.

4.4 parts of a-( l ,4,5,6-tetrahydro-2 pyrimidinylaminomethyl)benzylalcohol are stirred and cooled to 0C. While keeping the temperature at0C, there are added portionwise l6.5 parts of sulfuric acid solution80%. Upon completion, the whole is stirred for 2hr. 30 minutes at roomtemperature. The reaction mixture is poured onto crushed ice, treatedwith activated charcoal, filtered and the filtrate is made stronglyalkaline with a l0N sodium hydroxide solution. The product is extractedwith methylene chloride (three times 40 parts). The extract is dried andevaporated. The solid residue is treated with a small amount of acetoneand the product in base form is filtered off again and converted intothe hydrochloride salt of 2,3,5,6,7,- 8-hexahydro-3-phenylimidazo[l,2-a]pyrimidine; m.p. 188C.

EXAMPLE XI To a stirred solution of I39 parts of 2,4-dibromoacetophenone in 120 parts of acetone are added portionwise 8.75parts of 2-(N-benzylamino)-2- imidazoline. Upon completion, stirring iscontinued for 2 days at room temperature. The precipitated product isfiltered off, washed with acetone, dried and crystallized from ethanol,yielding Z-[N-benzyl-N-(Z- imidazolin-2-yl)amino]-4-bromoacetophenonehydro bromide, m.p. 262.9C.

To a stirred suspension of 5.5 parts of 2-[N-benzyl-N-(2-imidazolin-2-yl)amino]-4-bromoacetophenone hydrobromide in parts ofethanol is added portionwise 0.45 parts of sodium borohydride at roomtemperature. Upon completion, stirring is contined overnight (about l6hours). The reaction mixture is diluted with 50 partsof water and theethanol is distilled off in vacuo. The residue is extracted withchloroform. The latter is dried and evaporated. The residue is convertedinto the hydrochloride salt in 2-propanol, yielding a-[N-benzyl-N-(2-imidazolin-2yl)aminomethyl1-pbromobenzylalcohol hydrochloridehemiisopropyl alcoholate, m.p. 148.4C.

A mixture of 1.87 parts of a-[N-benzyl-N-( 2-imidazolin-Z-yl)aminomethyl]-p-bromobenzylalcohol and 27 parts ofsulfuric acid 80% is stirred for 2 hours at room temperature. Thereaction mixture is poured onto crushed ice. The whole is alkalized withsodium hydroxide solution and the product in base form is extracted withtoluene. The latter is dried, filtered and evaporated. The residue isconverted into the oxalate salt in 2-propanol. The crude salt isfiltered off and crystallized from Z-propanol, yieldingl-benzyl-3-(pbromophenyl)-2,3,5,6-tetrahydro-lH-imidazo[1,2- a]imidazoleoxalate, m.p. l44.8C.

EXAMPLE X]! A mixture of 8 parts of a-(2-aminoethyl)benzylalcohol, 6.5parts of 2-(nitramino)-2-imidazoline and 40 parts of xylene is stirredand refluxed for 3 hours with water-separator. The reaction mixture iscooled and the separated oily product is dissolved in 4-methyl-2-pentanone. The solvent is evaporated in vacuo, yieldinga-{2-[N-(2-imidazolin-2-yl)amino]ethyl}benzylalcohol as a residue.

A mixture of 8 parts of a-{2-[N-(2-imidazolin-2-yl)amino]ethyl}benzylalcohol from the preceding step and 36 parts ofsulfuric acid 80% is stirred for 3 hours at room temperature. Thereaction mixture is poured onto crushed ice and the resulting solutionis allowed to stand overnight at room temperature. It is then alkalizedwith sodium hydroxide solution and the product is extracted withtoluene. The extract is dried, filtered and evaporated. The residue istriturated in acetone. The solid product is filtered off andcrystallized from acetone, yielding 2,3,5,6,7,8-hexahydro-5-phenylimidazo[ l,2-a]pyrimidine; m.p. 145.5C.

EXAM PLE Xlll I A mixture of 2 parts of a-[Z-(l,4, Yd Qpyrimidinylamino)ethyl]benzylalcohol and 27 parts of sulfuric acid 80%is stirred for 2 hours at room temperature. The reaction mixture ispoured onto crushed ice and the whole is alkalized with sodium hydroxidesolution. The product is extracted with toluene. The organic layer isseparated, dried, filtered and evaporated. The solid residue iscrystallized from acetone, yielding3,4,6,7,8.9-hexahydro-6-phenyl-2H-pyrimido[1,2- a]pyrimidine, m.p.l77-l79C.

EXAMPLE XIV A solution of 6.1 parts of 2-aminoethanol in 16 parts ofmethanol and 40 parts of ether is cooled on ice. Then there is addeddropwise at about 5C. a solution of 18.4 parts ofo-chloro-a-nitrostyrene in 60 parts of ether. Upon completion, stirringin an ice-bath is continued for 1 hour. The reaction mixture isacidified with an excess of 2-propanol previously saturated with gaseoushydrogen chloride. The precipitated product is filtered off, washedthoroughly with ether and dried, yielding2-{N-[o-chloro-a-(nitromethyl)benzyl]amino- }ethanol hydrochloride.

To a mixture of 26 parts of 2-{N-[o-chloro-a-(nitrdmethyl)benzyl]amino}ethanol hydrochloride and 2 parts ofRaney-Nickel catalyst is added 120 parts of methanol (cooled in amixture of methanol/carbon dioxide), followed by the addition of 20parts of carbon dioxide. The whole is hydrogenated at 50 lbs/sq. inchpressure over 2 hours. The catalyst is filtered off and the filtrate isacidified with an excess of 2-propanol previously saturated with gaseoushydrogen chloride. The precipitated salt is filtered off, washed withmethanol and dried, yielding 2-{N-[a-(aminomethyl)-ochlorobenzyl]amino}ethanol dihydrochloride.

To a stirred mixture of 5.75 parts of 2-{N-[a-(aminomethyl)-o-chlorobenzyl]amino }ethanol dihydrochloride, 8 parts ofethanol and 6 parts of water is added 4 parts of sodium hydroxidesolution ION. To the resulting clear solution are added dropwise 1.68parts of carbon disulfide and the whole is stirred and refluxed for 1hour. After the addition of 0.2 parts of hydrochloric acid solution lON,stirring and refluxing is continued for 5 hours. The reaction mixture iscooled to room temperature and the precipitated product is filtered off.It is washed successively with a mixture of water and ethanol (1:1 byvolume), with ethanol and with water, and dried. The product iscrystallized from ethanol, yielding imidazolidineethanol; m.p. 169. 1 C.

A mixture of 12.84 parts of 4-(0-chlorophenyl)-2-thio-3imidazolidineethanol, 7.81 parts of methyl iodide and 40 parts ofmethanol is stirred for 4 hours at 40C. Diisopropylether is added andthe solvent is decanted, yielding S-(o-chlorophenyl)-2-(methylthio)-2-imidazoline-l-ethanol hydroiodide as an oily residue.

A mixture of 18.3 parts of 5-(o-chlorophenyl)-2-(methylthio)-2-imidazo1ine-lethanol hydroiodide and 40 parts of methanolsaturated with ammonia is stirred. 50

and refluxed for 2 hours. The solvent is evaporated and the solidresidue is treated with 20 parts of 2-propanol. The product is filteredoff and recrystallized from 50 parts of water, yielding2-amino-5-(o-chlorophenyl)-2- imidazoline-l-ethanol hydroiodide, m.p.181.6C.

A mixture of 4.15 parts of2-amino-5-(ochlorophenyl)-2-imidazoline-l-ethanol hydrochloride in 22.5parts of chloroform is treated with 3.6 parts of thionyl chloride andthe whole is stirred at reflux tem perature for 30 minutes. The solventis evaporated and the residue is taken up in 15 parts of chloroform. Thelatter is evaporated again, yielding 2-amino-1-(2-chloroethyl)--(o-chlorophenyl)-2-imidazoline hydrochloride as a residue.

To a stirred solution of 4.6 parts of 2-amino-l-(2-chloroethyl)-5-(o-chlorophenyl)-2-imidazoline hydrochloride in 12 partsof methanol is added a solution of 0.725 parts of sodium in 12 parts ofmethanol. The

whole is stirred and refluxed for 1 hr. 30 minutes. The reaction mixtureis evaporated and to the residue is added 50 parts of water and a smallamount of a N sodium hydroxide solution. The product is extracted twicewith 40 parts of methylene chloride. The combined extracts are dried,filtered and evaporated. The residue is converted into the hydrochloridesalt in 2- propanol and diisopropylether. The salt is filtered off,washed with acetone and dried, yielding5-(ochlorophenyl)-2,3,5,6-tetrahydro-1H-imidazo[1,2- a]imidazolehydrochloride; m.p. 215-222C.

EXAMPLE XV To a stirred solution of 10.7 parts of (:)-2,3,5,6-tetrahydro-S-phenyl-l H-imidazo[ l ,2-a]imidazole in parts of methanolis added a warm solution of 8.6 parts of (+)-tartaric acid in 20 partsof methanol. The whole is diluted ,with 80 parts of acetone and theproduct is allowed to crystallize. The precipitated fraction is fil- 0tered off [about 5.6 parts of crude (+)-2,3,5,6-

4-(o-chlorophenyl)2-thio-3- 4O tetrahydro-S-phenyl-l H-imidazo[1,2-a]imidazole (+)-tartrate a( 1% MeOH): +87.3] and set aside. Thefiltrate is evaporated in vacuo. The residue is dissolved in water andthe free base is liberated. It is extracted with chloroform and thelatter is dried and evaporated. The residue is dissolved in 28 parts ofmethanol and to this soltuion is added a warm solution of 5.7 parts of()-tartaric acid in parts of methanol. The product is allowed tocrystallize. It is filtered off and recrystallized from a mixture of 8parts of methanol and 16 parts of acetone till a constant rotation,yielding about 4.3 parts of (-)-2,3 ,5 ,6-tetrahydro-5-phenyll H-imidazol l ,2-a]imidazole()-tartrate; a( 1% MeOH -89.97. A sample of 4.2parts of ()-2,3,5,6- tetrahydro-S-phenyl-l H-imidazo[ 1,2-a]imidazole()-tartrate is dissolved in water and the free base is liberated. Afterextraction with chloroform, the latter is dried and evaporated. Theresidue is crystallized from acetone, yielding about 0.7 parts of(-)-2,3,5,6- tetrahydro-S-phenyl-l H-imidazo[ l ,2-a]-imidazole; m.p.l53.2C.; a( 1% MeOH): -21. l.49. The free base together with the residueof the evaporated motherliquor is converted into the hydrochloride saltyielding about 1.9 parts of (-)-2,3,5,6-tetrahydro-5-phenyl-lH- imidazo[l ,2-alimidazole hydrochloride; m.p. 277.lC.; a( 1% MeOH): l15.79.

The first precipitated product of about 5.6 parts which was set aside iscrystallized from a mixture of 8' parts of methanol and 16 parts ofacetone till constant rotation, yielding about 3.5 parts of (+)-2,3,5,6-

tetrahydro-S-phenyll H-imidazo[ l ,2-a]imidazole (+)-tartrate, 0z(1%MeOH): +88.83, is dissolved in water and the free base is liberated.After extraction with chloroform, the latter is dried and evaporated.The residue is crystallized from acetone, yielding about 1 part of(+)-2,3,5,6-tetrahydro-5-phenyl-lH- imidazo[l,2-a]imidazole; m.p.152.6C.; a(1% MeOl-l): +2 1 441. The free base together with the residueof the evaporated mother-liquor is converted into the hydrochloride saltin 2-propanol, yielding about 1.5 parts of(+)-2,3,5,6-tetrahydro-5-phenyl-l H- imidazol l ,2-a1imidazolehydrochloride; m.p. 277.3C.; a( 1% MeOH): +1 14.41".

EXAMPLE XVl The procedure of Example X may be followed to prepare the2,3,5,6,7,8-hexahydro-3-Ar-imidazo[1,2-

16 a]pyrimidines of formula (l). For example, by substi-6-(4-bromophenyl)-3,4,6,7,8,9-hexahydro-2H- tuting an equivalentquantity of the 4-Br-, 4-Me-, 4-Et-, pyrimido[ l ,2-a]pyrimidine;3,4,-di-Clderivative of a-(aminomethyl)benzyl alco-3,4,6,7,8,9-hexahydro-6-(4-methylphenyl)-2H- hol for thering-unsubstituted benzyl alcohol used pyrimido[ l ,2-a]pyrimidine; andtherein, the following respective products are obtained: 5 6-(3,4-dichlorophenyl)-3,4,6,7,8,9-hexahydro-2H-3-(4-brom0phenyl)-2,3,5,6,7,8-hexahydropyrimido[ l ,2-a1pyrimidine.

imidazo[ l ,2-a]-pyrimidine; We claim:2,3,5,6,7,8-hexahydr0-3-(4-methylphenyl)- l. A member selected from thegroup of compounds imidaz0[ l ,2a]-pyrimidine; having the formula:

F T" N Ar CH In N \N )n [N7kN R l 1 i 1 R R3-(4-ethylphenyl)-2,3,5,6,7,8-hexahydroand the therapeutically activeacid addition salts therof,

imidazo[l,2-a]-pyrimidine; and wherein:3-(3,4-dichlorophenyl)-2,3,5,6,7,8-hexahydro- R is a member selectedfrom the group consisting of imidozo[1,2-a]pyrimidine. hydrogen andbenzyl;

R is a member selected from the group consisting of EXAMPLE hydrogen andloweralkyl; and The procedure of Example XI may be follow d t Ar is amember selected from the group consisting of prepare the compounds offormula (I) wherein R is phenyl, loweralkylphenyl, halophenyl anddibenzyl. For example, by utilizing as starting materials halophenyl. arespective equivalent amount each of an appropriate A member Selectedfrom the group of compounds compound of formulas (VI) and (VII), thefollowing having the ula respective products are obtained in the form ofan oxal-b:flZy|-3-(3,4-dlChi0lOphCllyi)-2,3,5,()-lClr1lhydr0 lH-imidazoll ,2-alimidazolc; l-benzyl-3-(p-bromophenyl)-2,3,5,6,7,8-hexahydro- ""hlH-imidazo[ l ,2-a1pyrimidine;l-benzyl-3-phenyl-2,3,5,6,7,8-hexahydro-lH- i q1 2 40 and thetherapeutically active acid addition salts 1- 1 3 4 7 3 9 h 2 thereof,wherein Ar is a member selected from the mio[l,2-a]pyrimidine. groupconsisting of phenyl, loweralkylphenyl, halophenyl and di-halophenyl.

EXAMPLE 3. 2,3,5,6-Tetrahydro-5-phenyl-lH-imidazo[l,2- The procedure ofExample XII-may be followed to alimidazmeprepare the2,3,5,6,7,8-hexahydro-5-Ar-imidazo[1,2- -P "Y imidazo[ l ,2-a1imidazole.

5. 5-(3,4-Dichlor0phenyl)-2,3,5,6-tetrahydro-lH- imidazo[ l,2-a]imidazole.

a]pyrimidines of formula (I). For example, by substituting an equivalentamount of the 4-Cl-, 4-Meand 3,4-di-Cl derivatives ofa-(2-aminoethyl)benzyl alcohol for the ring-unsubstituted benzyl alcoholused y y therein, the following respective products are obtained:imidazol l ,z-alimidalole- 5-(4-chlorophenyl )-2,3 ,5 ,6,7,8-hexahydro--(pp y ,3,5 ,6- rahyd 0-l imidazo[ l ,2-a]pyrimidine; imidaZOl 1 l2,3,5,6,7,8-h h d -5-(5 h h 8. 2,3,5,6-Tetrahydro-5-m-tolyll H-imidazo[l ,2-

imidazoll,2-a1pyrimidine; and illimidfllole- 5-(3,4-dichlorophenyl)-2,3,5,6,7,8-hexhydro- P Y )-2.3,5. y

imidazol l ,2-alpyrimidine. imidazol l ,2-alimidazolc.

' l0. 2,3,5,6-Tetrahydro-3-p-tolyl-lH-imidazo[1,2- EXAMPLE XIXa]imidazole.

The procedure of Example Xlll may be followed to yl-3-(pp ny t t ahyprepare the 3 ,4,6,7,8,9-hexahydro-6-Ar-2H- 1H4midal0l r l pyrimido[l,2-a]pyrimidines of formula (I). For exam- P y y ple, by substitutingan equivalent amount of the 4-Br-, imidalol l r fi 4-Me-, and3,4-di-Clderivatives of a-(2-aminoethyl)- l3. r y 'p benzyl alcohol forthe ring-unsubstituted benzyl alcoimidaZ0[l,2-a]imidaZ01ehol usedtherein, the following respective products are 14. (H- aydr0-5-phenyl-lH- obtained: imidazo[ l ,2-a]imidazole. I

15. A chemical compound having the formulas 16- A chemical compoundhaving the formula:

l\ Ll l l I A L v u l H/ iiCli-Cri l i"-CH R C-Ar f I N I it iil benzylwherein: '0 wherein:

R is a member selected from the group consisting of R is a memberselected from the group consisting of hydrogen and benzyl; hydrogen andloweralkyl; and R, is a member selected from the group consisting of Aris a member selected from the group consisting of hydrogen andloweralkyl; and phenyl, loweralkylphenyl, halophenyl and di- Ar is amember selected from the group consisting of halophenyl.

phenyl, loweralkylphenyl, halophenyl and dihalophenyl.

UNITED sTATEs PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION 3,865. 836 February 11, 1975 PATENT NO.

DATED 'NVENTOMS): Van Gelder, Josephus Ludovicus Hubertus et a1 It iscertified that error appears in the ahoveidentified patent and that saidLetters Patent are hereby corrected as shown below:

In Claim I, the formula as shown- Should be Signed and Sealed this RUTHMASON .4 Ilvxling Officer C. MARSHALL DANN (mmnm'imu'r uj' lun'ms and'l'rurIcmur/rx

1. A MEMBER SELECTED FROM THE GROUP OF COMPOUND HAVING THE FORMULA:
 2. Amember selected from the group of compounds having the formula: 3.2,3,5,6-Tetrahydro-5-phenyl-1H-imidazo(1,2-a)imidazole. 4.2,3,5,6-Tetrahydro-2-methyl-3-phenyl-1H-imidazo(1,2-a)imidazole. 5.5-(3,4-Dichlorophenyl)-2,3,5,6-tetrahydro-1H-imidazo(1,2-a)imidazole. 6.5(p-Fluorophenyl)-2,3,5,6-tetrahydro-1H-imidazo(1,2-a)imidazole. 7.5-(p-Chlorophenyl)-2,3,5,6-tetrahydro-1H-imidazo(1,2-a)imidazole. 8.2,3,5,6-Tetrahydro-5-m-tolyl-1H-imidazo(1,2-a)imidazole. 9.5-(m-Chlorophenyl)-2,3,5,6-tetrahydro-1H-imidazo(1,2-a)imidazole. 10.2,3,5,6-Tetrahydro-3-p-tolyl-1H-imidazo(1,2-a)imidazole. 11.1-Benzyl-3-(p-bromophenyl)-2,3,5,6-tetrahydro-1H-imidazo(1,2-a)imidazole. 12.5-(o-Chlorophenyl)-2,3,5,6-tetrahydro-1H-imidazo(1,2-a)imidazole. 13.(-)-2,3,5,6-Tetrahydro-5-phenyl-1H-imidazo(1,2-a)imidazole. 14.(+)-2,3,5,6-Tetrahydro-5-phenyl-1H-imidazo(1,2-a)imidazole.
 15. Achemical compound having the formula:
 16. A chemical compound having theformula: